It is particularly preferred to employ Staphylococcal genes and gene products as targets for the development of antibiotics. The Staphylococci make up a medically important genera of microbes. They are known to produce two types of disease, invasive and toxigenic. Invasive infections are characterized generally by abscess formation effecting both skin surfaces and deep tissues. S. aureus is the second leading cause of bacteremia in cancer patients. Osteomyelitis, septic arthritis, septic thrombophlebitis and acute bacterial endocarditis are also relatively common. There are at least three clinical conditions resulting from the toxigenic properties of Staphylococci. The manifestation of these diseases result from the actions of exotoxins as opposed to tissue invasion and bacteremia. These conditions include: Staphylococcal food poisoning, scalded skin syndrome and toxic shock syndrome.
The frequency of Staphylococcus aureus infections has risen dramatically in the past 20 years. This has been attributed to the emergence of multiply antibiotic resistant strains and an increasing population of people with weakened immune systems. It is no longer uncommon to isolate Staphylococcus aureus strains which are resistant to some or all of the standard antibiotics. This has created a demand for both new anti-microbial agents and diagnostic tests for this organism.
Clearly, there is a need for factors, such as the novel compounds of the invention, that have a present benefit of being useful to screen compounds for antibiotic activity. Such factors are also useful to determine their role in pathogenesis of infection, dysfunction and disease. There is also a need for identification and characterization of such factors and their antagonists and agonists which can play a role in preventing, ameliorating or correcting infections, dysfunctions or diseases.
A target that would be useful in developing such factors are teichoic acids, which are polymers found in the cell walls of Gram-positive bacteria. Teichoic acids have been shown to be essential for viability and normal morphogenesis of several Gram-positive species. CDP-glycerol:poly(glycerophosphate) glycerophospho transferase is a key enzyme in the wall teichoic acids biosynthetic pathway. The gene is named tarF in S. aureus, which makes the ribitol-based polymer, and tagF in Bacillus subtilis, which make the glycerol-based polymer. The enzyme adds CDP-activated glycerol in the final step of synthesis of the lipid-linked linkage unit on which the polymer is synthesised. Mutation of this gene has been shown to be lethal in Bacillus subtilis and Staphylococcus aureus and will prevent the synthesis of wall teichoic acids, which are essential for the viability of Gram-positive cells. Although there are many types of wall teichoic acids in bacteria, the linkage unit structure is conserved in most species tested, and thus inhibition of this enzyme is a valid antibacterial strategy.
The polypeptides of the invention have amino acid sequence homology to a known Bacillus subtilis tagF protein. See Briehl et al. 1989. "Mutants of Bacillus subtilis 168 thermosensitive for growth and wall teichoic acid synthesis" J. Gen. Microbiol. 135:1325-1334; GenBank Accession Number X15200.